Why Can't We Prevent Alzheimer's?

In my day job, I investigate the role of RNA in Alzheimer’s disease. I work on computer problems. One of these problems is how RNA is processed in Alzheimer’s brains. RNA is tailored by seamstresses in our cells, leading to many species or “isoforms” of RNA and protein. I like to think of these isoforms as tiny dresses. A single gene can be patterned to build many styles of a dress. And some RNA can regulate other RNA, tuning its expression “up” or “down,” deciding how many dresses are made. Furthermore, a series of “epigenetic” molecules attaches to the structure of the genome and switch genes “on” or “off.” Thus, our genes are regulated by disparate forces, which decide when, which, and how many of these dresses are sewn in the cellular factory.

Alzheimer’s research is undergoing a shift to a “systems” or “networks” approach, where instead of just pinpointing a single mutation or genetic variant, we are now looking at networks—groups of molecules that go to work together on shifts on the cellular factory floor. We can see major shifts in RNA occurring in brain tissue, but the causes of these changes are often invisible to us. So far, a large component of it appears to us as Dark Matter.

The Small Species Camp

Alzheimer’s disease has, for decades, been dominated by the “amyloid cascade hypothesis,” the theory that large plaques of amyloid-beta (building up outside cells) and tau proteins (building up inside cells) starve and kill neurons.

Yet one emerging theory suggests that it’s the smaller forms of amyloid-beta molecules that cause all of the trouble. William L. Klein, a neurobiologist at the Cognitive Neurology and Alzheimer’s Disease Center at Northwestern University, is among the scientists credited with originating this “small species camp,” more technically known as the “Abeta oligomer cascade hypothesis.” His claim: A smaller form of amyloid beta, or “oligomer,” acts as a neurotoxin, adhering to cell receptors and jamming communication. Klein’s team found that they bind to a spot near a receptor in the hippocampus called NMDA, which has long been implicated in the creation of new long-term memories.

The NMDA receptor works like a tiny gate that opens and closes and lets ion signals jump from cell to cell. The toxins were binding to a spot near the receptor and keeping the gates jammed open (a “gain-of-function” disorder) disrupting proper cell-to-cell communication, and along with it the creation of new synapses, the ability to make new memories, and what neuroscientists call “plasticity.” In fact, the Federal Drug Administration approved an NMDA receptor inhibitor called Memantine in 2003 as a treatment for moderate to severe Alzheimer’s disease, but scientists were without good explanation for why it had modest benefits.

Klein’s team introduced more evidence for this theory when he showed that this small species toxin was binding to a complex that reduced the function of an insulin receptor. Insulin uptake is needed for the creation of long-term memories. Indeed, Alzheimer’s is now thought of, by some, as a form of diabetes, or Diabetes Type 3. (Suzanne Craft at the Wake Forest School of Medicine is now leading a trial on the effects of insulin nose spray on Alzheimer’s.)

Tiny Garbage Men

An intriguing new trend in modern medicine is technology that calls the body’s own defense systems to the task of fighting diseases. In cancer research, the “immunotherapeutic approach” is back in vogue. Alzheimer’s research has a similar vanguard of drug candidates.

The idea with these candidates is to stimulate the body’s own waste disposal systems to swab the sticky plaques out of the brain on their own. Some Alzheimer’s researchers say they can now jumpstart the waste disposal systems, sort of like giving the body’s own tiny garbage men a pay hike to do their job better.

At least two research groups have demonstrated the power of this strategy. A few years ago, J. Paul Taylor, a former assistant professor of neurology at University of Pennsylvania, published findings that modulating the expression of a certain gene, which alters epigenetic code, could reduce or accelerate plaque buildup in the eyes of fruit flies. Ben Bahr, a chemist at University of North Carolina-Pembroke, and Dennis Wright, a chemist at University of Connecticut-Storrs, are the cofounders of Synaptic Dynamics. They discovered a compound that could increase the function of one of the tiny garbage men in the cell, a lysosome, which lassos old proteins and dissolves them with enzymes. In fact, the group showed it could clear amyloid beta species proteins by 63 to 73 percent in Alzheimer’s disease model mice, and it improved cognitive functioning.

There is no mainstay drug yet, but science is on the march. Researchers like me continue to investigate the mysterious non-coding RNA. Ben Bahr’s group said it would stimulate the brain’s lysosome to clean up plaques in the brain. Suzanne Craft is setting out to prove that she could treat the disease with an insulin nose spray. William Klein is developing the first antibody to target the “small species” of the protein residues.

I traveled to visit my father in Chicago. He told me that he had finished writing a play. It was about a man who had a scar high on his cheekbone, which he got when he crashed through a storefront window the day he learned he was going to have a son. The man had not always been the best father. He was tired and despondent, but he never developed dementia. Though old, he never lost his senses. When his son went to visit him, the man locked the door. But his son broke down the door, and he told his father how important he had been. And that he needed him. 

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Jim Kozubek is a science writer and computational biologist based in Cambridge, Massachusetts.

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